In 1950, his first short story, “The Last Christmas,” was published in American Vanguard. After the war, he wrote his first book, The Dark Arena, which was published in 1955.

In 1960, Bruce Jay Friedman hired Puzo as an assistant editor of a group of men’s pulp magazine with titles such as Male, Men. Under the pen name Mario Cleri, Puzo wrote World War II adventure features for magazine True Action.

In 1969, Puzo’s most well-known work, The Godfather (1969) was published. Puzo stated this story came from research into organized crime, not from personal experience, and was looking to write something that would appeal to the masses. The novel remained on The New York Times Best Seller list for 67 weeks and sold over nine million copies in two years. The book was later developed into the film The Godfather (1972), directed by Francis Ford Coppola. The film received three awards of the eleven Oscar category nominations, including Puzo’s Oscar for Best Adapted Screenplay. Coppola and Puzo then collaborated on sequels to the original film, The Godfather Part II (1974) and The Godfather Part III (1990).

Puzo was born in the Hell’s Kitchen area of New York City to Italian immigrants from Pietradefusi, Province of Avellino, Campania. When Puzo was 12, his father, who worked as a trackman for the New York Central Railroad, left his family, and his wife Maria was forced to raise their seven children. He served in the US Army Air Forces in Germany in World War II, and later graduated from the City College of New York. Puzo married a German woman, Erika, with whom he had five children. When Erika died of breast cancer at the age of 58 in 1978, her nurse, Carol Gino, became Puzo’s companion.

In 1991, Puzo’s speculative fiction The Fourth K was published; it hypothesizes a member of the Kennedy family who becomes President of the United States early in the 2000s.

Puzo died of heart failure on July 2, 1999 at his home in Bay Shore, New York, at the age of 78.

Coppola and Puzo preferred the title The Death of Michael Corleone for the third film, but Paramount Pictures found that unacceptable. In September 2020, for the film’s 30th anniversary, it was announced that a new cut of the film titled Mario Puzo’s The Godfather, Coda: The Death of Michael Corleone will have a limited theatrical release in December 2020 followed by digital and Blu-ray.